Abstract Plant-based diets are associated with intestinal health; however, in many cases, the bioactive components within plant diets that confer these impacts have not been identified. MicroRNAs (miRNAs) are evolutionarily conserved single-stranded, noncoding RNAs that can regulate gene expression. Mammalian exosomes (lipid-based nanoparticles) encapsulate miRNAs and are shed from almost all cell types to interact with specific target cells. Plant-derived exosome-like nanoparticles (ELNs) have been characterized, are structurally similar to mammalian exosomes, and mediate transport of various compounds including proteins and miRNAs. A recent study suggests species-specific edible ELNs target particular microbes in the gut to impact microbial composition and gut function. We have developed exquisitely sensitive biological reagents to address the hypothesis that dietary plant RNAs, such as miRNAs, directly impact the microbiome and gut health. Our miRNA of interest is miR-146a, a mammalian miRNA that plays critical roles in innate immunity, inflammation, antiviral responses, and cancer. Our focus is on the role of miR- 146a in intestinal homeostasis through microbiome modulation. We maintain mice deficient in miR-146a, and established assays document that this deficiency alters microbiome populations and tolerance to bacterial infections. We have engineered a series of isogenic plants expressing either empty vector (control) or the murine miR-146a. If plant specific ELNs differentially modulate this response, we posit diets composed of different crops expressing miR-146a will differentially impact the microbial composition and gut health of miR-146a deficient mice. Our combined scientific expertise and precision tools in plant genetics, mouse models and microbiome science provide a powerful opportunity to address if dietary miRNAs impact intestinal homeostasis through microbiome-mediated mechanisms.